Novel compound halts cocaine addiction and relapse behaviors

New research published by Jun-Xu Li in the UB Department of Pharmacology and Toxicology and his colleagues demonstrates that a novel compound dramatically blocked cocaine’s rewarding effects and markedly blunted cocaine relapse in animals.

“This is the first systematic study to convincingly show that RO5263397 has the potential to treat cocaine addiction.”

Jun-Xu Li, assistant professor of pharmacology and toxicology

University at Buffalo

BUFFALO, N.Y. – A novel compound that targets an important
brain receptor has a dramatic effect against a host of cocaine
addiction behaviors, including relapse behavior, a University at
Buffalo animal study has found.

The research provides strong evidence that this may be a novel
lead compound for treating cocaine addiction, for which no
effective medications exist.

The UB research was published as an online preview article
in Neuropsychopharmacology last week.

In the study, the compound, RO5263397, severely blunted a broad
range of cocaine addiction behaviors.

“This is the first systematic study to convincingly show
that RO5263397 has the potential to treat cocaine addiction,”
said Jun-Xu Li, MD, PhD, senior author and assistant professor of
pharmacology and toxicology in the UB School of Medicine and
Biomedical Sciences.

“Our research shows that trace amine associated receptor 1
– TAAR 1—holds great promise as a novel drug target for
the development of novel medications for cocaine addiction,”
he said.

TAAR 1 is a novel receptor in the brain that is activated by
minute amounts of brain chemicals called trace amines.

The findings are especially important, Li added, since despite
many years of research, there are no effective medications for
treating cocaine addiction.

The compound targets TAAR 1, which is expressed in key drug
reward and addiction regions of the brain.

“Because TAAR 1 anatomically and neurochemically is
closely related to dopamine – one of the key molecules in the
brain that contributes to cocaine addiction – and is thought
to be a ‘brake’ on dopamine activity, drugs that
stimulate TAAR 1 may be able to counteract cocaine
addiction,” Li explained.

The UB research tested this hypothesis by using a newly
developed TAAR 1 agonist RO5263397, a drug that stimulates TAAR 1
receptors, in animal models of human cocaine abuse.

One of the ways that researchers test the rewarding effects of
cocaine in animals is called conditioned place preference. In this
type of test, the animal’s persistence in returning to, or
staying at, a physical location where the drug was given, is
interpreted as indicating that the drug has rewarding effects.

“When we give the rats RO5263397, they no longer perceive
cocaine rewarding, suggesting that the primary effect that drives
cocaine addiction in humans has been blunted,” said Li.

The compound also markedly blunted cocaine relapse in the
animals.

“Cocaine users often stay clean for some time, but may
relapse when they re-experience cocaine or hang out in the old
cocaine use environments,” said Li. “We found that
RO5263397 markedly blocked the effect of cocaine or cocaine-related
cues for priming relapse behavior.

“Also, when we measured how hard the animals are willing
to work to get an injection of cocaine, RO5263397 reduced the
animals’ motivation to get cocaine,” said Li.
“This compound makes rats less willing to work for cocaine,
which led to decreased cocaine use.”

The UB researchers plan to continue studying RO5263397,
especially its effectiveness and mechanisms in curbing relapse to
cocaine addiction.

In addition to Li, co-authors are David A. Thorn, a technician
and PhD candidate; Li Jing, PhD, postdoctoral fellow, Yanyan Qiu,
research scientist, Amy M. Gancarz-Kausch, PhD, postdoctoral
fellow, and David M. Dietz, PhD, assistant professor, all of the UB
Department of Pharmacology and Toxicology; Chad M. Galuska, PhD, of
the College of Charleston; and Yanan Zhang, PhD, of Research
Triangle Institute.